Several alpha(2)-adrenoceptor antagonists have inverse agonist properties i
n cell culture systems, usually expressing high levels or a constitutively
active form of alpha(2)-adrenoceptors. In characterizing the binding of a,
adrenoceptor agonists to rat brain tissue sections, we found that condition
s known to alter agonist affinity for these receptors, particularly the add
ition of 100 mu M GTP, altered the binding of the alpha(2)-adrenoceptor ant
agonist [H-3](1,4-benzodioxan-2-methoxy-2-yl)-2-imidazoline hydrochloride (
RX821002). In further studies, we found that under our conditions [H-3]RX82
1002 demonstrates inverse agonist properties at alpha(2)-adrenoceptors. Thi
s is the first demonstration of inverse agonism at alpha(2)-adrenoceptors i
n native tissue. We found that the alpha(2)-adrenoceptor antagonist, (2S,12
bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octahydro-2H-benzo(b)furo(2,3-a)
quinazoline)-2,4'-pyrimidin-2'-one (MK-912), did not have clearly discernib
le inverse agonist properties and acted as a neutral antagonist in these st
udies. On the other hand, the antagonist rauwolscine actually displayed par
tial agonist properties in our studies. These findings indicate that the in
verse agonist properties of alpha(2)-adrenoceptor antagonists can be demons
trated in native tissue, as well as in tissue culture, and they strengthen
the idea that inverse agonist properties may be of physiological and pharma
cological importance. (C) 2000 Elsevier Science B.V. All rights reserved.